Abstract

Wnt pathway deregulation is a common characteristic of many
cancers. Only colorectal cancer predominantly harbours mutations
in APC, whereas other cancer types (hepatocellular carcinoma,
solid pseudopapillary tumours of the pancreas) have activating
mutations in b-catenin (CTNNB1). We have compared the dynamics
and the potency of b-catenin mutations in vivo. Within the murine
small intestine (SI), an activating mutation of b-catenin took much
longer to achieve Wnt deregulation and acquire a crypt-progenitor
cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a
single activating mutation of b-catenin was unable to drive Wnt
deregulation or induce the CPC phenotype. This ability of b-catenin
mutation to differentially transform the SI versus the colon correlated
with higher expression of E-cadherin and a higher number of
E-cadherin: b-catenin complexes at the membrane. Reduction in
E-cadherin synergised with an activating mutation of b-catenin
resulting in a rapid CPC phenotype within the SI and colon. Thus,
there is a threshold of b-catenin that is required to drive transformation,
and E-cadherin can act as a buffer to sequester mutated
b-catenin.